The
sodium-hydrogen exchanger-isotype 1 (NHE-1) plays a critical role in
myocardial ischemia-
reperfusion injury. While studies employing less selective
sodium-
hydrogen inhibitors have demonstrated antiarrhythmic activity, only one study has examined the in vivo efficacy of selective NHE-1 inhibition in a canine model of
ischemia-reperfusion-induced
arrhythmia. In the present study, the antiarrhythmic activity of
Benzamide, N-(aminoiminomethyl)-4-¿4-(2-furanylcarbonyl)-1-piperazinyl -3-(methy lsulfonyl),
methanesulfonate (
BIIB 513), a novel NHE-1 inhibitor, was examined. An in vivo canine model of
myocardial ischemia-
reperfusion injury in which 60 min of left anterior descending coronary artery (LAD) occlusion followed by 3 h of reperfusion was employed.
BIIB 513 was infused either prior to
ischemia or prior to reperfusion. Arrhythmias were quantified by single lead electrocardiogram.
Infarct size, determined by
triphenyltetrazolium staining, was expressed as a percent of the area-at-risk. In vivo, NHE-1 inhibition did not affect phase 1a arrhythmias, which occur within the first 10 min of occlusion, however,
BIIB 513 significantly reduced the incidence of
ischemia-induced phase 1b arrhythmias which occur between 10 and 30 min following occlusion and the incidence of reperfusion-induced
ventricular fibrillation. Furthermore, NHE-1 inhibition significantly reduced
infarct size, when the
drug was administered either prior to
ischemia or prior to reperfusion. NHE-1 inhibition selectively reduces both
ischemia-induced phase 1b arrhythmias and reperfusion-induced
ventricular fibrillation, and also markedly reduces
myocardial infarct size when the
drug is administered prior to
ischemia or prior to reperfusion.